Halogenated phenacylpyridines



Patented Sept. 20, 1949 ,UNITEDSTAIES 2 Y 2 I! I 2,482,521

nALooENA'rEornsmrornmmmmss James M. Smith, Jr; :North rriainfiemgnc 1;, lassignor to American Cyanamid"'Q6mpany,. New

, York, N. Y.,a corporation'of-Maine' No Drawing.

ApplicationsJamlary 24 1-1947, Serial No. 724mm 51Claims.. (Cl. 260-287) This;inventionarelates to new organic compoundssandto methods of preparing the same.v The :applicationis: a; continuation --in--part; of my application; Serial: Number 598,627, filed-June. 9 1945 nowwPatentNumber 2 142,865. 7

The new compounds of the present invention mayW-be. illustrated-by the ,-followinggeneral formula:

Compoundshaving the above formula maybe 2 prepared .by' treating a compound havingthe formula-lR-.H2?OR with ahalogen; such asbromine .or chlorine; while suspended or 'dis'- solved ina suitableorganic liquid at temperatures of from about 10 0. to 100 0., preferably b8. tween 20- andSQ- C. Thenresulting. product which is halogenated. at the omega position may be used directly; oritsmay'beisolated by precipita-a tion upon: dilution .ofthe solvent withwater or'by evaporation of. thecsolvent, as illustratedzi-n the specific examples.

Among the. phenacylpyridines which maybe halogenatedat the. omega position in accordance; Withth-e. process of? the present invention-are such phenacylpyridines as Z-(p-chlorophenacyl) pyr-i dine, 2--(o;-ch1orophenacyl) Pyridine; 2-(m.-chlo-- rophenaeyl pyridine; 2- (p-bromo-phenacyl)- pyridine,v Z-(p-iodophenacyl) pyridine; 2.-(o-dich1orophenacyl): :pyridine; 2- (p-chlorophenacyl) 5, 6- benzopyridine; 4 (p,-brom0phenacy1-) -5; 6-benzo.-' pyridine;...2 methyl-6'- tp-chloroph'enacyl) pyridine, l-methyl-Z-(p-chlorophenacyl) pyridine, 4,6-dimethyl-ZAp-chlorophenacyl) pyridine; 2- methyl -.5ethyl.- 6-- (p-bromophenacyll pyridine, and. other phenacylpyridines having' alkyl or alkylene substituents on the.- pyridine .ringand one. or. more, halogens: on the benzene ring To. properly halogenate the phenacylpyridine at the omegaposition I use a substantially equimolar proportion. of the halogen; that is, about two equivalents of halogen fork-each mole otthephen aeylpyridine. If a. large excess of: halogenatingagentis used, for example, more'than10%;.ofgtha v 21 theoretical requirements, the yield. of. pure prod.- uct is greatlyizeduccd.

..As..sol:..'ents for thelreacti'onzthere be used.

glacial. acetieacid, .trichlorethylei-ie,- ethylene-Qdi- 'chloride ,..diethyl. other; dibutyl .etheig; chloroform,

carbon disuliida. alcohokand other organic. liquids. whichlareesubstantially inert. totin v halogenating agent underi conditions. of :the reaction. ,In. gen- ,eral', the presence of water is to be avoided-asz it tendsltocause hydrolysis resulting. splitting oi the; phenacylpyr-idine; Of the various solvents, I greatlyprefer. to useglacialaceticacid although ether; is; preferred when .halogenatingmephenacyl benzopyr-idine.

Although: the: reaction vproceeds rapidly and reaches-a substantial de ree. ofcompletion within: a, few minutesrparticularly whenausinachlorine at ropmtemperaturait mayzbe. advisable, and-will: do. no harm; :to allow the reactants: tdremain v in. contact. for: several. hours. I

lhe invention will betill-ustratedin. greater detail by means oi the; iol-lowingsspecificl examples which representative phenacylpyridinesx are. halogenated in: the omega: position tosprod uce-the new-compounds. of the presentinvention- Itis tobe understoodzthatztheseiexamples are. intended to illustrate rtrhe? invention and-are. not in? limitatiorr-thereotsince,..obviously, certaimcha nges maybamade therein byzthose skilled; i-rrtheart. -All partsrareby weight :unless otherwise indicated. Inasmuehr as.ithe phenacylpyridineshaving, halogems-ubsti-tuents .onthe: benzeneiringare-alsonew compounds; 1 the preparation starts with known: intermediates. The 1-(halophenyl-l-Z-(pyridyl)- acetylzen-eseare :claimedlinsmyw copending applica tienr.SeriahNumben'l25fl22 'filed Jan.- .31; L947;

. Example I 7 I v. Av ,rnixture. oi-

par-ts.ofi-pechlorobenzalda hylzle, 9.9.0: parts of. alpha-picoline,:-and l,fi88.parts of. aceticanhydride areheatedundenrefluxin an atmospheresof. nitrogenlfor. 18 hours. Low-boil ing products and unreacted. ingredients are them removed. by. vacuums-distillation until. approXimately 1,5QOLpartsoi distillateare obtained. The

residue isppoured intoi. several volumes of-cold imately 1,245 parts. Purification of the product may be accomplished by recrystallization of the base or its hydrochloride from a suitable organic solvent such as alcohol with the aid of decolorizing charcoal, or by vacuum distillation of the base, which boils at 173-180 C./-7 mm. The purified base melts at 83-84 C., and the hydrochloride melts at 193195 C.

To a solution of 550 parts of crude l-(pchlorop henyl) -2-(2-pyridyl) ethylene in 2,850 parts 'of chloroform at 60 C. is added a solution of 408 parts of bromine in 600 parts of chloroform over approximately an hours time. Refluxing is continued for an additional half hour, and the mixture is then allowed to stand overnight at room temperature. A white precipitate forms slowly, which is filtered oil the neXt day after cooling the reaction mixture in an ice bath. Ap-

proximately 680 parts of 1,2-dibromo-l-(pchlorophenyl) -2-(2-pyridyl) ethane is obtained, which Inelts at 174-l75 C. An additional 125 parts of product can be obtained by distilling off part of the chloroform from the mother liquor, yielding a dark brown solid which can be purified by recrystallization from chloroform or other organic solvent. A hydrochloride of the base can be prepared by the addition of alcoholic H01 to a solution of the base in alcohol. This melts at 183-484 C.

To "a solution of 658 parts of potassium hydroxide (86% real) in 3,950 parts of alcohol is added 1,263 parts of 1,2-dibromo-1-(p-chlorophenyl) -2-(2-pyridyl) ethane. This mixture is heated under reflux for one hour, and then filtered hot from potassium bromide. The filtrate is then cooled in an ice bath, resulting in the formation of a crystalline precipitate, which is ill-- tered ofi, washed with cold alcohol, and dried at 45 C. This represents approximately 282 parts of 1-(p-chlorophenyD-2-(2 pyridyl)-acetylene with a crude melting point of 98.6-100 C. The addition of several volumes of water to the mother liquor results in the precipitation of 400 parts of a light tan solid which melts at 50-80 C. On recrystallization of this material from alcohol, approximately 100 additional parts of l-(pchlorophenyl) -2 (2-pyridyl)-acetylene can be obtained. The purified base melts at 99-1005 C.

To a mixture of 1,400 parts of water and 2,590 parts of 95% sulfuric acid at 125 C. is added 300 parts of 1-(p-ohlorophenyl) -2-(2-pyridyl) acetylene. The mixture is rapidly heated to refluxing (142 C.) and held there for five minutes, after whichit is cooled and diluted with several volumes of ice water. It is then neutralized with caustic, resulting in the formation of a greenishyellow precipitate. This is filtered off at room temperature, Washed well with water, and dried at 45 C. Approximately 310 parts of 2-(pchlorophenacyl)pyridine is obtained which, after recrystallizing from dilute alcohol, melts at 86-87.6 C. The hydrochlor-ide'can be prepared by dissOlVing the base in alcohol and adding an equivalent amount of alcoholic hydrogen chloride. Addition of ether slowly precipitates the hydrochloride as a white solid melting at 1765-180 C.

To a solution of 220 parts of 2-(p-ohlorophenlac'yllpyridine in 925 parts of glacial acetic acid at 18 C. is added a solution of 152 parts of bromine in 157 parts of glacial acetic acid over a 75 minute period. The mixture is then allowed to stir at room temperature for about 'four hours. A cream-colored precipitate forms slowly, which is filtered off, washed with ether, and dried. A yield of approximately 353 parts of 2-(w-bromoethylene hydrobromide.

4 p-chlorophenacyl)pyridine hydrobromide is obtained, which melts at 172-175 C. (doc). In water the hydrobromide hydrolyzes to the corresponding base, which can be recrystallized from alcohol, and melts at 97-98 C.

Example II A mixture of 600 parts of p-chlorobenzaldehyde, 396 parts of gamma-picoline, and 435 parts of acetic anhydride are heated to refluxing in an atmosphere of nitrogen for six hours. On cooling, a crystalline mass is formed, which is drowned in several volumes of water and filtered. The press cake is dissolved in an excess of warm dilute hydrochloric acid and filtered from a small amount of insoluble material. On cooling to 10 C. a heavy precipitate is formed, which is filtered ofi and then slurried in acetone to remove dark colored impurities. On refiltering and drying, approximately 671 parts of l-(p-chlorophenyD- 2-(4-pyridyl)ethylene hydrochloride is obtained, which is a yellow product melting at 248249--250 C. The free base, prepared by neutralizing an aqueous solution of the hydrochloride with caustic, melts at approximately- To a solution of ten parts of l-(p-chlorophenyl)-2-(4-pyridyl)-ethyl-ene in 52.5 parts of glacial acetic acid at room temperature is added a solution of 7.44 parts of bromine in 10 parts of glacial acetic acid over a half hour period. A thick orange precipitate is formed immediately. The mixture is then heated to refluxing, giving momentary complete solution followed by repre- =cipitation, and held there for 1.5 hours, after which it is allowed to stand overnight. Upon filtering and 'drying, approximately 16.5 parts of a product which probably is l-(p-chlorophenyb- (lor 2-bromo) -2 (4-pyridyl) ethylene hydrobromide is obtained, which melts with decomposition at 275280 C.

To a solution of 3.9 parts of potassium hydroxide in 24 parts of alcohol is added 7.5 parts of l- (p-chlorophenyl) (1- or 2-bromo) -2-(4-pyridyl) The mixture is refluxed for 1.5 hours and filtered hot from potassium bromide. Upon cooling to 0 C., a crystalline precipitate of l-(p-chlorophenyl) -2- l-pyridyl) acetylene is formed, which upon recrystallization from alcohol melts at 119.5-122 C.

To a mixture of 38 parts of water and 68 parts of sulfuric acid is added 8 parts of 1- (p-chlorophenyl) -2-(4 pyridyl) acetylene. This is heated to refluxing (142 C.) and held there for five minutes. The mixture is cooled and diluted with several volumes of water, followed by neutralization with caustic. A heavy yellow precipitate is formed, which is filtered ofi at room temperature and washed with water. On drying, 8.3 parts of 4-(p-chlorophenacyl)pyridine is obtained, representing a quantitative yield. Upon recrystallization from alcohol, bright yellow crystals are obtained which dry to a yellow-tan product melting at 94.5-96" C.

To a solution of 2.46 parts of 4-(p-chlorophenacyDpyridine in 10.5 parts of glacial acetic acid at 20 C. is added dropwise a solution of 1;70 g. bromine in 2 arts of glacial acetic acid. A precipitate forms as the bromine hits the solution, which immediately redissolves, giving a clear light yellow solution. Shortly after the addition is complete, a cream colored crystalline precipitate begins to form. Precipitation is completed with the aid of ether, and the product filtered ofi, washed with ether, and dried. Approximately 4.16 parts of 4(w-bromo-p-chlorophenacyl)pyridine vhydrobromide are obtained melting at 223-224-228" 0., representing a quantitative yield.

Example III A mixture of 760 parts quinaldine (95% Reilly Tar and Chemical Co.), 530 parts p-chlorobenzaldehyde, and 357 parts acetic anhydride are boiled under reflux for 2.5 hours under an atmosphere of nitrogen. The solution is allowed to cool, whereupon it solidifies. After 16 hours it is melted and poured into ice and water to give about 4 liters total volume. The crude product is collected on the filter and washed free of acid. It is then extracted with 6,300 parts of boiling alcohol containing a little activated carbon. The alcohol extract on filtering and cooling deposits a yellow crystalline product which is collected on the filter, washed with alcohol and dried. The filtrate and washings are used to extract the crude residue three timee more in a similar way. The total recovery is 654 parts. For analysis a small sample of this materia1 was recrystallized from boiling alcohol; it is then melted at 142.8-143.2 C.

A mixture of 26.6 parts of 2-(p-chlorostyryl) quinoline and 222 parts of o-dichlorobenzene is heated to 50 C. until complete solution occurs. It is then cooled to 25 C. and 17 parts of bromine in 46 parts of o-dichloro-benzene is added; the temperature is raised to 180-190" C. and the solution boiled under reflux for two hours. It is then cooled and the precipitate is collected on the filter, washed with o-dichlorobenzene and ether and dried. The yield is 30 parts melting at 199-199.9 C.

Five parts of the brominated product above is treated with 5 parts of potassium hydroxide in 24 parts of alcohol at the boil for one hour. The

mixture is filtered hot and the filtrate cooled to give 1 part of light brown product melting at 137-1375 C.

Five parts of the acetylene prepared as above is treated with 15.6 parts of 65% sulfuric acid at 6 the boil for five minutes. On cooling, dilution to 100 parts by'volume and neutralization with ammonia, brilliant greenish-yellow colored 2-(pchlorophenacyhquinoline is obtained, melting at 140.2-141" C.

2-(p-chlorophenacyl)quinoline is dissolved in alcohol and treated with the equivalent amount of bromine (1 mol for 1 mol) at room temperature. After about 30 minutes the solution is diluted with water and the w-bromo compound precipitates. It is collected on the filter and dried at C. The melting point is 103-105 C.

1. Compounds having the general formula RCH- UJR in which X is a halogen, R is. a member of the group consisting of pyridine, benzopyridine and alkylpyridine radicals, and R is a halogenated aryl radical.

2. Compounds having the general formula Br 0 R(|]H'-.(3

in which R is a pyridine radical.

3. 2- (w-bromo-p-ch1orophenacyl) pyridine. 4. 4- (w-bromo-p-chlorophenacyl) pyridine. 5. 2-(w-bromo-p-chlorophenacyl) quinoline.

JAMES M. SMITH, JR.

REFERENCES CITED Beilstein, Vierte Auflage, vol. '7; pp. 210, 218, 221, 225, 234., and 235.

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